Millions of human patients suffer from viral infection or viral wart infection, demodex infection, fungal or yeast infection, or bacterial infection of the skin, hair follicle, or genitalia. Viral or wart infection, demodex infection, fungal or yeast infection, or bacterial infection of the eyelids, conjunctiva, cornea, ocular surface or Meibomian glands, can manifest as blepharitis—an inflammatory condition of the eyelid.
Verruca vulgaris, the medical term for wart, can arise anywhere on the body and serves as an umbrella term for all warts. Warts can result from viral infections that are most often associated with Human Papilloma Virus (HPV) or Molluscum Contagiosum Virus (MCV).
Human papilloma viruses (HPV) are a large group of approximately 100 genotypes of DNA tumor viruses that infect the epithelia of skin or mucosa and cause warts. Verruca vulgares (common warts) present clinically as hyperkeratotic, exophytic and dome-shaped papules or nodules associated with HPV-1, 2 or 4. They are most commonly found on fingers, dorsal hands, and other sites prone to trauma such as knees or elbows, but they may occur in any anatomic location.
Genital infection with HPV can result from intimate contact with individuals harboring clinical or subclinical HPV infection, and is one of the most common sexually transmitted diseases among adolescents and adults. Prevalence of HPV infection in the adult population differs depending upon geographical location, but typically ranges from 20% to 45% of all populations. In the US, 20 million people have genital HPV infection at any given time, amounting to an annual cost burden of $6 billion per year in healthcare dollars spent for sexually transmitted infections (second only to HIV).
Non-genital viral infections of the skin may occur via direct person-to-person skin contact, or indirectly through contaminated surfaces in a publicly accessed area, such as a public swimming pool or gymnasium. The skin is exposed to the virus through minor abrasions and infection is promoted via maceration of the epithelia. Autoinoculation is common as well. Non-genital varieties of skin warts occur in 20% of schoolchildren with equal frequency in both sexes.
Verruca palmares et plantares (palm and sole warts) are thick, endophytic papules and plaques with numerous thrombosed capillaries that often coalesce into large dome-like elevations. They are often painful due to deep inward growth and are notoriously difficult to eradicate. HPV-1, 2, 27 and 57 are the most common culprits of palm or sole warts.
Verrucae plana (flat warts) are skin-colored or pink, smooth-surfaced, slightly elevated and flat-topped papules most commonly located on the dorsal hands, legs, or face. They are often in a linear array as scratching or shaving can spread them. HPV types 3 and 10 cause this phenotype.
Condyloma acuminata (genital warts) are found on the external genitalia and perineum, perianal, or in adjacent areas such as the inguinal folds or mons pubis. They can range in size from a few millimeters to centimeters and are most commonly sessile, smooth-surfaced exophytic papillomas that can be skin colored, brown or white. They lack the thick hyperkeratotic layer of common warts found on skin. HPV-6 and 11 cause genital warts in the majority of cases.
Infection of the skin surrounding or forming part of the eye can also occur. Blepharitis is a commonly encountered condition affecting approximately 15% of the population, and represents an inflammatory condition of the eyelids. Blepharitis may involve the dermis, eyelashes, tarsal conjunctiva, mucocutaneous junction or meibomian glands and is most often caused by gram positive bacterial infection, such as Stapylococcus, Corynebacterium, and Pripionibacterium species. However, other agents causing blepharitis include viral, demodex (mite), or yeast infections, seborrhea, rosacea, and hormonal dysregulation.
Left untreated, blepharitis may cause dry eye exacerbation, loss of cilia, corneal ulceration, and impart increased risk of endophthalmitis after cataract surgery. For facility in understanding, it is commonly compartmentalized into inflammation affecting the structures of the anterior, posterior lid margin or both.
Anterior blepharitis most commonly presents as anterior lid and lash crusting with or without the presence of collarettes. Other manifesations may also include skin or lash flaking associated with seborrhea or angular inflammation particular to Moraxella or virus.
Posterior blepharitis is also commonly referred to as meibomian gland disease. Meibomian glands are responsible for the release of lipids into the tear film, effectively mitigating evaporative tear loss. Besides the chronic irritation, inflammation and erythema common to all blepharitis, the posterior variant may further be characterized by inspissation of the meibomian glands, keratinization of orifices, telangiectasia, and posterior margin lid thickening. Bacterial lipases stemming from the ocular flora may also act upon meibomian secretions creating free fatty acids which further disturb the ocular surface.
Current treatments for bacterial, demodex, fungal/yeast, and viral infections, including warts and ophthalmic conditions such as blepharitis, can be ineffective in that they treat only a subset of the causative agent of the infection. Many of the current treatments incorporate undesirable ingredients, such as steroids or other potentially harmful components.
A recent discovery by Capriotti, et al., has disclosed compositions comprising an iodophor, such as povidone-iodine (PVP-I) as an active ingredient, and dimethyl sulfoxide (DMSO) used as a penetration enhancer for the active ingredient. These compositions were shown to be useful for treating fungal infections of the skin and nails. See, e.g., US Publication No. US2014/0205559 (Capriotti '559), which is incorporated herein by reference in its entirety. PVP-I is a well-known antiseptic with a broad spectrum of activity against viral, fungal, and bacterial species, as well as demodex, and has no known bacterial, fungal or viral resistance. PVP-I has also been shown to inhibit the formation of biofilms and to eliminate biofilms that have already formed.
A variety of organic solvents, including dimethyl sulfoxide (DMSO), are known to enhance the percutaneous absorption of certain medicaments. The superiority of DMSO to other solvents for enhancing penetration and dermal retention was demonstrated in a study of the passage of 14C-labelled griseofulvin, dissolved in DMSO, dimethylacetamide, dimethylformamide, alcohol or benzene, through human skin in vitro. The ratio of penetration of griseofulvin in the various solvents was 60, 40, 7, 3, and 1, respectively. Even when a 50% solution of DMSO in water was used, the rate of penetration of 14C-hydrocortisone was markedly enhanced. Nevertheless, it has been a long-accepted in the pharmaceutical arts that DMSO enhances penetration for small molecules or low molecular weight (LMW) compounds or drugs, but does not enhance penetration of high molecular weight (HMW) compounds greater than about 10,000 Daltons, such as polymers.
It has been surprisingly discovered that DMSO is effective at enhancing penetration into the thick stratum corneum of the palms and soles. Moreover, DMSO has been only recently, and unexpectedly, been demonstrated to enhance penetration of povidone-iodine (PVP-I). PVP-I preparations range in molecular weights from 1,000 to 1,000,000 or more. Topical pharmaceutical compositions have been approved using only PVP grades K29-32. One acceptable PVP grade is PVP K30, which has a MW of 30,000 to 60,000 daltons (average MW of about 40,000 daltons). Accordingly, prior to the teachings of Capriotti '559, one skilled in the art would not employ DMSO in a topical pharmaceutical composition to enhance skin penetration of large molecules, polymers or high-molecular weight substances such as PVP-I.
Even in view of the teachings of Capriotti '559, however, it was unknown that particular topical gel formulations comprising an iodophor, such as PVP-I, in DMSO were particularly useful in treating certain viral, demodex, fungal/yeast, or bacterial infections manifesting as skin infections (e.g., warts) or ophthalmic conditions (e.g., blepharitis). Thus, the current invention is a significant advance to the art, and discloses the surprising and unexpected discovery that a topical gel composition comprising an iodophor such as PVP-I, DMSO, and a gelling agent can provide advantageous and unexpected results in the treatment of warts or other skin infections, including skin infection of the eye such as blepharitis.